Invasion and proliferation kinetics in enhancing gliomas predict IDH1 mutation status

Abstract

Background: Glioblastomas with a specific mutation in the isocitrate dehydrogenase 1 (IDH1) gene have a better prognosis than gliomas with wild-type IDH1.

Methods: Here we compare the IDH1 mutational status in 172 contrast-enhancing glioma patients with the invasion profile generated by a patient-specific mathematical model we developed based on MR imaging.

Results: We show that IDH1-mutated contrast-enhancing gliomas were relatively more invasive than wild-type IDH1 for all 172 contrast-enhancing gliomas as well as the subset of 158 histologically confirmed glioblastomas. The appearance of this relatively increased, model-predicted invasive profile appears to be determined more by a lower model-predicted net proliferation rate rather than an increased model-predicted dispersal rate of the glioma cells. Receiver operator curve analysis of the model-predicted MRI-based invasion profile revealed an area under the curve of 0.91, indicative of a predictive relationship. The robustness of this relationship was tested by cross-validation analysis of the invasion profile as a predictive metric for IDH1 status.

Conclusions: The strong correlation between IDH1 mutation status and the MRI-based invasion profile suggests that use of our tumor growth model may lead to noninvasive clinical detection of IDH1 mutation status and thus lead to better treatment planning, particularly prior to surgical resection, for contrast-enhancing gliomas.

Keywords: IDH1; glioma; growth kinetics; invasion; mathematical model; patient-specific; proliferation.

Fig. 1.

MRI scans from 2 patients with similar ρ values, one that is mutant for IDH1 (top row: A,B,C) and one that is IDH1 wild-type (bottom row: D,E,F). All 6 images are pretreatment scans; A and D are T1Gd images, B and E are T2 images, and C and F are false-color images representing tumor cell density overlaid on the T1Gd scans (red, highest cell density; blue, lowest cell density). The growth parameters associated with these GBMs are ρ = 21.1/year, D = 85.0 mm²/year, with ρ/D = 0.25/mm² for the IDH1mut tumor and ρ = 21.0/year, D = 14.0 mm²/year, ρ/D = 1.5/mm² for the IDH1wt tumor. The figure illustrates the more diffuse nature of the IDH1 mutant tumor (top row) versus the wild-type (bottom row).

Fig. 2.

A plot of ρ/D values for the 42 IDH1 wild-type and 11 IDH1 mutant contrast-enhancing gliomas in this study. The mean values of ρ/D are 5.0409/mm² for IDH1 wild-type and 0.181/mm² for IDH1 mutant, which are significantly different (P = .0057).

Fig. 3.

(A) A plot of ρ versus D for the 39 patients with contrast-enhancing gliomas, from whom these values were obtainable. There is an apparent segregation of the IDH1 mutant tumors from the IDH1 wild-type tumors with IDH1mut tumors having lower ρ values than IDH1wt tumors. The apparent segregation is not significant; crossmatch analysis of the 2 groupings yielded an approximate P value of .231. (B) Tumor growth velocity plotted against ρ/D for both IDH1 wild-type (n = 32) and IDH1 mutant (n = 7) contrast-enhancing gliomas. The IDH1wt tumors have larger ρ/D values and populate the graph both above and below the value of ρ/D = 1, while the IDH1mut tumors have lower ρ/D values and populate the graph below the value of ρ/D = 1, mirroring the differences in ρ/D values that were seen in Fig. 2. There was no statistical difference in mean velocities between IDH1wt and IDH1mut tumors for any given value of ρ/D (IDH1 wt: mean, 59.83 mm/y; median, 34.43; standard deviation 101.5); (IDH1 mut: mean, 48.91 mm/y; median, 60.66; standard deviation 28.2) (P = .632).

Fig. 4.

Separate plots of ρ values (A) and D values (B) for IDH1 wild-type tumors (n = 32) and IDH1 mutant tumors (n = 7). IDH1wt tumors are shown on the left in both A and B, while IDH1mut tumors are shown on the right in both A and B. In A, the mean proliferation rates, (ρ) are significantly different: IDH1wt (both grades) = 29.22/year, IDH1mut (both grades) = 11.87/year, P = .046. In B, the mean invasion rates (D) are not significantly different: IDH1wt (both grades) = 41.24 mm²/year; IDH1mut (both grades) = 53.83 mm²/year, P = .503.

Fig. 5.

Kaplan-Meier survival curves for IDH1wt and IDH1mut glioma patients. The median survival of IDH1wt glioma patients (573 days) was significantly different from that of IDH1mut glioma patients (896 days) (P = .0047).

Fig. 6.

Receiver operating characteristic (ROC) analysis of ρ/D as a predictor of IDH1 mutation status. True positive rate versus false positive rate for various cutoff values of ρ/D are tested and plotted as sensitivity (y-axis) and an indicator of specificity (x-axis). The resulting area under the curve (AUC) is 0.90765, where an AUC of 1.0 indicates a predictive accuracy of 100%.